Date of Completion

11-5-2018

Embargo Period

11-2-2018

Keywords

metallothionein chemotaxis immunology

Major Advisor

Dr. Michael A Lynes

Associate Advisor

Dr. Adam Zweifach

Associate Advisor

Dr. Charles Giardina

Associate Advisor

Dr. Andrew Wiemer

Associate Advisor

Dr. Victoria Robinson

Field of Study

Cell Biology

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Metallothionein (MT) is a cysteine rich stress response protein that lacks a signal peptide and thus has historically been considered an intracellular protein. However, the presence of MT in a variety of extracellular fluids and spaces suggests an additional extracellular role for this protein. We have shown that MT released in the extracellular environment can bind to the surface of lymphocytes and is a chemoattractant for Jurkat T cells among other cells. Additionally, when Jurkat T cells are pre-incubated with MT, there is a decline in the subsequent chemotactic response to SDF-1 α. Jurkat T cells pre-incubation with SDF-1 α can similarly block the chemotactic response to MT, suggesting a common interaction of these two proteins with SDF-1 α’ s cognate receptor CXCR4. The chemotactic response to MT can be blocked with antagonists of G-protein coupled receptors (e.g. cholera toxin and pertussis toxin), AMD3100 (antagonist of CXCR4) as well inhibitors of the specific GPCR-dependent signaling components Arp2/3 and Phospholipase C. The N terminal region of MT is important for interaction with the receptor as chemotaxis studies using 10-mer MT peptides showed that two of these peptides (MT1-10 and MT4-12) can interfere with the chemotactic response of Jurkat T cells to SDF-1 α. MT pre-incubation significantly interfered with the RAW 264.7 cell response to CCL2 as well as U937 cell response to RANTES suggesting that the MT chemotactic effect is not limited to one specific receptor. Hence, dysregulation and cellular release of MT during toxicant exposure, chronic inflammation and autoimmune disease may represent an unexpected immunomodulatory danger signal and an opportunity to exploit this phenomenon to develop new avenues for therapeutic intervention.

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